ADP acting on P2Y13 receptors is a negative feedback pathway for ATP release from human red blood cells.

Red blood cells may regulate tissue circulation and O2 delivery by releasing the vasodilator ATP in response to hypoxia. When released extracellularly, ATP is rapidly degraded to ADP in the circulation by ectonucleotidases. In this study, we show that ADP acting on P2Y13 receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release. mRNA of the ADP receptor P2Y13 was highly expressed in human red blood cells and reticulocytes. The stable ADP analogue 2-MeSADP decreased ATP release from red blood cells by inhibition of cAMP. The P2Y12 and P2Y13 receptor antagonist AR-C67085 (30 micromol/L), but not the P2Y1 blocker MRS2179, inhibited the effects of 2-MeSADP. At doses where AR-C67085 only blocks P2Y12 (100 nmol/L), it had no effect. AR-C67085 and the nucleotidase apyrase increased cAMP per se, indicating a constant cAMP inhibitory effect of endogenous extracellular ADP. 2-MeSADP reduced plasma ATP concentrations in an in vivo pig model. Our results indicate that the ATP degradation product ADP inhibits ATP release by acting on the red blood cell P2Y13 receptor. This negative feedback system could be important in the control of plasma ATP levels and tissue circulation.